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Equipment, Quality
Assurance & Validation
Programme
Peter Yap
17 October 2014
Scope of Presentation
• Equipment in aseptic dispensing
– Laminar air flow cabinets
– Isolators
• Quality Assurance
• Validation Programme
Sterile Compounding
• Sterile compounding by pharmacies in hospital
and ambulatory care centres since late 1980s
in Singapore
– Laminar flow technology >20 years
– Barrier-isolation technology >15 years
Sterile Compounding
• Commonly referred guidelines:
– USP Chapter 797
– ASHP Guidelines on Handling Hazardous Drugs
Am J Health-Syst Pharm—Vol 63 Jun 15, 2006
– ISOPP Standards of Practice
J Oncol Pharm Pract 2007; 13; No.3 Suppl
– Pharmaceutical Inspection Convention (PIC/S)
PI 007-6 (1 January 2011)
http://www.picscheme.org/pdf/26_pi007-6recommendationonasepticprocesses.pdf
Equipment in Aseptic Dispensing
• Basic premise
– Protection of the raw material & final product
– Personnel protection
– Environment protection (for hazardous
products)
Laminar Air Flow Cabinets
Two types of LAFC
• Horizontal Flow Cabinet
• Vertical Flow Cabinet
Horizontal Flow Cabinet
• Used for most sterile product preparations
because they do not require expensive venting
to outside air
• Protects object but not the operator
• Should NOT be used for handling aerosols,
cytotoxics, or any other substances that may
pose a threat to the well-being of the operator
Vertical Flow Cabinet
• In aseptic dispensing, usually refers to
Cytotoxic Drug Safety Cabinets (CDSC) or
Biological Safety Cabinets (BSC) used in the
preparation of cytotoxic drugs
• Protects both object and operator
Cytotoxic Drug Safety Cabinets
• Class II containment workstations
Designed to provide three types of protection:
Personnel protection from material inside the
cabinet
Protection for the material inside of the cabinet
Protection for the environment from the material
inside of the cabinet
BSC - Class I
• Designed to provide personnel and
environmental protection only
• Product inside the cabinet is not protected and
thus subject to contamination.
BSC- Class II
• Class II cabinets meet requirements for
the protection of personnel, product
and the environment
• 4 subtypes- A, B1, B2, and B3; each
differentiated according to the method
by which air volumes are recirculated or
exhausted
4 subtypes- A, B1, B2, and B3
• Class II, Type A Cabinets
– Not vented
• Class II, type B1 Cabinets
– must be vented; 30% of the air is exhausted from the cabinet
while 70% is recirculated back into the room.
• Class II, type B2 Cabinets
– must be totally exhausted; 100% of the air from the cabinet is
exhausted through a dedicated duct.
• Class II, type B3 Cabinets
– must be vented; 70% of the air is exhausted from the cabinet
while 30% is recirculated.
CDSC versus BSC Class II
Isolators versus CDSCs (Cytotoxic Drug Safety Cabinets) Melvyn Davis. ISOPP XIII
Parts of an Isolator
Exhaust
Work Areas
HEPA Filters
Transfer hatch
Gloves Port
Barrier Isolator Technology
- History of use in pharmacy
• 1980s
• Early1990s
• Mid1990s
• Mid 1990s
• 2000s
First available in Europe
Preferred ‘enclosure’ in UK and Ireland
Introduced/Used in USA
Introduced/Used in Singapore
Introduced/Used in Thailand & Malaysia
Barrier Isolator Technology
Exhaust
HEPA filter
• Developed to remove operator from the
environment in which products are
prepared  eliminating source of
contamination
• Enclosed, ventilated, controlled
environment (vertical laminar or
turbulent airflow)
• Access is through transfer hatch/
chamber; operation conducted through
fixed-glove access
• Good aseptic technique and support
materials are required
Physical Structure
• Hard shell
– Hard Plastic
– Plexiglass
– Stainless Steel
• Soft shell
– Soft Plastic Film
Am J Health-Syst Pharm –Vol 57 Feb 15, 2000
Transfer technologies
• Offers means of introducing materials into
work areas without compromising internal
integrity of system
• Selection based on the level of protection
needed
– Simple transfer hatches
– Laminar-airflow interfaces
– Timed air lock
Interaction Technologies
• Allows operator to interact with
the process or equipment
contained in barrier system
– Gloves ports
– Half-suits
Interaction Technologies
- Gloves ports
• Sleeves-and-gloves
arrangement
- One piece system
• Higher integrity but more
expensive
- Two-piece system
• Better fit for gloves
• Less expensive
Interaction Technologies
- Half suits
• Developed to increase lifting
capabilities and expand areas of
reach within work areas.
• Disadvantages:
– Difficulty in cleaning
– Difficulty in entering and exiting
– Hygiene issues with multiple users
Optional Features…
• Inner doors released by foot
switches
• Sliding transfer chamber tray
• Adjustable height
• CCTV monitoring system
• Easy Change Cuff Ring System
Recommendations
• National Institute for Occupational Safety and Health (NIOSH)
• American Society of Health-System Pharmacists (ASHP)
• International Society of Oncology Pharmacy Practitioners
(ISOPP)
When sterile hazardous drugs are being compounded,
use one of the following ventilated cabinets:
• CDSC
• BSC (Class II Type B2 is preferred)
• BSC (Class III)
• Isolators intended for asepsis and containment
(aseptic containment isolators)
Safety issues in CDSC, BSC and Isolators
• Staff must understand that effective
containment depends on:
– operators’ use of proper technique
– operators’ work practices
– operators’ housekeeping practices
CDSC versus ISOLATOR
Cost
Efficiency
- Cabinet
- Turn around time
- Consumables
- Minimal disruption
Safety
- People
- Product
- Environment
Key
consideration
in selection
- Maintenance
- Infrastructure
Others
Vendor support;
Functionality (Size,
Ergonomics, Heat, Noise,
lighting, cleaning)
CDSC versus ISOLATOR
Practice
Type
Space
Funding
Unresolved issues related to current
compounding practice
Exposure risks
- needle stick injuries
- Surface contamination
Cumulative strain disorders
PHARMACY STAFF
SAFETY/HEALTH
Preparation errors in
dosage/drug
PATIENT
SAFETY
Recruitment & Training
WORK
ORGANIZATION
Quality Assurance
• Programme for the systematic monitoring and
evaluation of the various aspects of a service
or facility to ensure that standards of quality
are met
• Provides confidence in a service &/or product
Aspects of Quality Assurance
Drug
Work
Processes
Quality
Assurance
Facilities &
Equipment
Personnel
Aspects of Quality Assurance
•
•
•
•
•
•
•
Policies & Procedures
Facilities & Equipment
Aseptic Techniques
Personnel education, training & evaluation
Processes
End-product testing & evaluation
…… and more……
Environmental Monitoring
• Designed to provide information
demonstrating that:
– Engineering controls
– Sanitization processes
– Work practices
Collectively provide an environment consistently
capable of maintaining acceptable microbial levels
Types of Activities Validated by Process Simulation Testing
Gowning & Gloving Procedures
Physical
Plant
Function
Per
Engineering
specification
Individual
Aseptic
Manipulations
Ability of compounding equipment
To produce aseptic product
Facility
Cleaning
Procedures
Types of Contamination
Intrinsic contamination
• Contamination having its source in the
manufacturing process
Extrinsic contamination
• Contamination occurring during preparation for use
or during administration
Sources of Extrinsic Contamination
• Environment
• Operator’s Techniques
• Materials used
- Drug additives
- Antiseptics employed
- Particulate matter
- Delivery system
Contamination risk from
Environment
• Microbial effect of air venting during IV fluid
administration was studied
• 203 infusion samples were studied (123 tests vs 80
controls)
• 32 (26%) in-use infusion fluids were contaminated vs
0 for unused solutions (p < 0.001)
• Bags with air vents more contaminated than those
without (27 vs 5, p<0.001)
Ref: Useh MF et al. East Afr Med J 1998 Jun;75(6):322-6
Contamination risk from
Environment
• Majority of agents: Gm positive organisms
• 57% of those who received contaminated
fluids developed septicaemia
• Creating air vents for introduction of
additives during IV fluid administration
provides routes of entry for micro-organisms
Ref: Useh MF et al. East Afr Med J 1998 Jun;75(6):322-6
Monitoring
• Temperature & relative humidity
• Air exchange, percentage of fresh air,
Pressure differential
• Particulates
• Microbial organisms
Non-Viable Particle Monitoring
• Verify air quality classification of primary
engineering controls (LAFC, Isolators)
• 2 – 4 times a year
• Usually outsourced to commercial companies
Microbiological Monitoring
• Required to demonstrate microbiological
cleanliness of cleanroom during
production
• Frequency usually given in standard
operating procedures
Microbiological Monitoring
• Air sampling
• Surface sampling
Microbiological Monitoring
Validation
Validation
• Often refers to personnel validation
• Assessment of aseptic processes
• Relies upon prospective, concurrent and also
involve re-validation
• Often involves the use of media fills (process
simulation studies)
Validation
• Growth Media
a) must be able to support growth of broad
spectrum of microorganisms likely to be
encountered
b) Triptone Soya Broth (TSB) commonly used
c) Positive control - must be able to support growth
when inoculated with the challenged
microorganisms
d) Negative control - to ensure that the growth media
used is sterile
Process Simulation Test
• Should follow as closely as possible the routine
aseptic manufacturing process
• All equipment (and conditions) should remain
the same
• Should represent a “worst case” situation and
include all manipulations and interventions likely
to be seen during a preparation
• “start-up” & “on-going” simulation test
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www.asia4safehandling.org